The long term goal of this proposal is to elucidate the molecular mechanisms whereby the IGF signaling axis contributes to the intiation and progression of prostate cancer in an autochthonous model system. To this end, three specific aims are proposed: 1) To test the hypothesis that expression of IGF-I by the prostate gland facilitates the progression of prostate cancer; 2) To test the hypothesis that a correlation exists between the level of serum IGF-I and the rate of initiation and/or progression of prostate cancer; and 3) To test the hypothesis that prostate specific abrogation of the IGF-I / IGF1R signaling axis inhibits the initiation and/or progression of prostate cancer. To accomplish the first specific aim, the consequence of prostate specific IGF-I transgene expression win be characterized with respect to time to palpable tumor, tumor grade and metastatic incidence in transgenic mice carrying a probasin (PB) directed DES-IGF-I transgene and in [PB-DES IGF-I X TRAMP]F1 mice. To accomplish the second specific aim, the consequence of elevated systemic IGF-I levels will be characterized with respect to time to palpable tumor, tumor grade and metastatic incidence in MT-GHRH transgenic mice, [MT-GHRH X TRAMP]F1, C3H mice and [TRAMP X C3H]F1 mice. To accomplish the third specific aim, the consequence of Cre/LoxP mediated prostate-specific ablation of IGF-I and IGF1R expression will be characterized with respect to time to palpable tumor, tumor grade and metastatic incidence in [TRAMP:LoxP-IGF-I:Cre] and [TRAMP:loxP-IGF1R:Cre] mice.